rs2287371

Positions:

• chr7-130440971-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_018718.3(CEP41):​c.-5A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,611,662 control chromosomes in the GnomAD database, including 148,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12784 hom., cov: 33)
  • Exomes 𝑓: 0.43 (135254 hom.)
• Consequence: CEP41 NM_018718.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.891

Genes affected

CEP41 (HGNC:12370): (centrosomal protein 41) This gene encodes a centrosomal and microtubule-binding protein which is predicted to have two coiled-coil domains and a rhodanese domain. In human retinal pigment epithelial cells the protein localized to centrioles and cilia. Mutations in this gene have been associated with Joubert Syndrome 15; an autosomal recessive ciliopathy and neurological disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 7-130440971-T-G is Benign according to our data. Variant chr7-130440971-T-G is described in ClinVar as [Benign]. Clinvar id is 261053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-130440971-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP41	NM_018718.3	c.-5A>C		5_prime_UTR_variant	1/11	ENST00000223208.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP41	ENST00000223208.10	c.-5A>C		5_prime_UTR_variant	1/11	1	NM_018718.3	P3

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60889 AN: 151990 Hom.: 12758 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.435

GnomAD3 exomes AF: 0.458 AC: 114309 AN: 249758 Hom.: 27525 AF XY: 0.458 AC XY: 61926 AN XY: 135146

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.466

Gnomad EAS exome AF: 0.658

Gnomad SAS exome AF: 0.552

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.425 AC: 620347 AN: 1459554 Hom.: 135254 Cov.: 43 AF XY: 0.428 AC XY: 310923 AN XY: 726204

Gnomad4 AFR exome AF: 0.303

Gnomad4 AMR exome AF: 0.567

Gnomad4 ASJ exome AF: 0.460

Gnomad4 EAS exome AF: 0.666

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.401 AC: 60964 AN: 152108 Hom.: 12784 Cov.: 33 AF XY: 0.405 AC XY: 30127 AN XY: 74352

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.661

Gnomad4 SAS AF: 0.560

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.440

Alfa AF: 0.413 Hom.: 19778

Bravo AF: 0.408

Asia WGS AF: 0.652 AC: 2262 AN: 3478

EpiCase AF: 0.406

EpiControl AF: 0.400

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Joubert syndrome 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2287371; hg19: chr7-130080812; COSMIC: COSV56221342; COSMIC: COSV56221342;